18, 20-epoxypregnene derivatives



pared using as starting material conessine.

United States Patent O 18,20-EPOXYPREGNENE DERIVATIVES Raphael Papp'o,Skokie, 111., assignor to G. 'D. Searle 8: Co., Chicago, Ill., acorporation of Delaware No Drawing. Application September 4, 1958 SerialNo. 758,920

7 Claims. (Cl. 260-43955) The present invention relates to a new groupof 18,20-epoxypregnene derivatives and, more particularly, to thecompounds of the structural formula 04H: \X CH3 wherein X is a member ofthe class consisting of CHCH2N(1OW6I alkyl, -OHOHz-:'(CH3)2 G(OH)GH3 andO=OH groups and to intermediates for their preparation, and especially18,20-epoxy-21-di(lower alkyDamino-5-pregnen-3-ols. The lower alkylgroups referred to hereinabove can be methyl, ethyl, straight-chain orbranched propyl, butyl, amyl and hexyl.

The compounds of this invention are valuable steroidal intermediates andhormonal agents. These epoxides are also barbiturate potentiators.Furthermore, the compounds in which X represents a CH-CH N(lower alkyl)group form quaternary ammonium salts with a 4 variety of organic estersof sulfuric, hydrohalic and aromatic sulfonic acids. Among such estersare methyl chloride, bromide and iodide; ethyl chloride, propylchloride, butyl bromide, isobutyl chloride, benzyl chloride, phenethylchloride, napthylmethyl chloride, dimethyl sulfate, methylbenzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin,propylene chlorohydrin, allyl chloride, methallyl bromide and crotylbromide. Such quaternary salts, and especially the methohalides, areganglion blocking agents. The 4-pregnen-3-ones of this invention alsocause sodium excretion and the 18,20- epoxy-20-hydroxy-4-pregnen-3-oneis a luteoid agent.

The compounds of this invention are conveniently pre- Conessine isreacted with aluminum chloride and sodium borohydride to prepare a boroncomplex which is then oxidized with chromium trioxide and acetic acid toyield 3-dimethylamino-6-oxoconanine. The latter is quaternized to formthe bismethiodide which is then converted to the bis-quatemaryhydroxide. The latter is then heated under anhydrous conditions to yield3,5-cyclo-18-di methylamino-20-pregnen-6-one. This compound can also beformed directly by refluxing the bismethiodide with an alkali metaltertiary 'alcoholate. This base is next quaternized, suitably usingmethyl p-toluenesulfonate. Subsequent treatment of the salt with osmiumtetroxide yields 3,5-cyclo-l8-trimethylammonium20,2l-dihydroxy-2,891,948 Patented June 23, 1959 ice pregnan-6-one p-toluenesulfonate.Treatment of this salt with an alkali metal tertiary alcoholate yields a3,5-cyc1o- 18,20-epoxy-2l-hydroxy-pregnan--one. This compound is acentral nervous depressant and specifically a barbiturate potentiator.Esterification of this alcohol with the p-toluenesulfonic acid andtreatment of the p-toluenesulfonate with a dialkylamine in acetonitrileand then with alkali yields the 3,5-cyclo-l8,20-epoxy-21-di(lower alkyl)aminopregnan-6-one of the structural formula These bases formmethohalides which are ganglion agents. Reduction with lithium aluminumhydride yields the corresponding 6-hydroxy compounds and themethohalides again are ganglion blocking agents. Treatment of the basefirst with formic acid and then with alkali yields the18,20-epoxy-2l-di(lower alkyl)amino-5-pregnen-3-ol which, on Oppena-ueroxidation forms the 18,20-epoxy- 21-di(loweralkyl)amino-4-pregnen-3-one. These compounds also form quaternary saltswhich are ganglion blocking agents. 7

Treatment of the l8,20-epoxy-21 dimethylaminolpregnen-3-one with aperoxy acid such as peroxybenzoic acid or hydrogen peroxide yields theN-oxide which on heating forms l8,20-epoxy-4,20-pregnadien-3-one. Thelatter, on treatment with aqueous acid, yields 18,20-epoxy-20-hydroxy-4-pregnen-3-one, a luteoid agent and an inhibitor ofdesoxycorticosterone.

3 ,5 -cyclo-1 8,20-epoxy-2 l-dimethylaminopregnan-6-one, on treatmentfirst with a peroxyacid and then with alkali yields the N-oxide which onheating, yields 3,5-cyclol8,20-epoxy-20-pregnen-6-one. The latter, upontreatment with aqueous acid yields 3,5-cyclo-18,20-epoxy-20-hydroxypregnan-6-one, a barbiturate potentiator.

The compounds which constitute this invention will appear in furtherdetail from the following examples which are given for the purpose ofillustration only and are not to be construed as limiting the inventionin spirit or in scope. in these examples quantities are indicated asparts by weight.

This application is a continuation-in-part of applicants co-pendingapplication Serial No. 736,963, filed May 22, 1958.

OHzN (alkyl) 5 Example 1 5 tate of sodium chloride. After standing for12 hours at room temperature the mixture is filtered and the sodiumchloride is washed with benzene. The combined filtrate and washings aretreated with excess aqueous sodium hydroxide and the organic layer isseparated by decanta tion. The aqueous layer is extracted with benzeneand the combined organic solutions are dried over anhydrous sodiumsulfate and concentrated under reduced pressure to a viscous gum. Theboron compound thus obtained is dissolved in 800 parts of acetic acidand, while agitated, is treated in the course of 7 hours by the gradualaddition of a solution of 200 parts of chromic anhydride in 200 parts ofwater While the temperature is maintained at 17 25 C. Agitation at roomtemperature is continued for 12 hours after which the mixture is stirredfor hours with 40 parts of 2-propanol and then concentrated underreduced pressure to a viscous residue which is diluted with water,cooled, stirred and treated by slow addition with an excess of a 40%aqueous sodium hydroxide solution. The deep green mixture is extractedrepeatedly with a mixture of ether in benzene. The combined organicsolutions are carefully washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure to dryness. The residueis dissolved in a minimum amount of benzene, filtered to remove someinsoluble material and the filtrate is taken to dryness to yieldcrystalline 3-dimethylamino-6-oxoconanine. The compound is sufficientlypure for the preparations described hereinbelow. Further purificationcan be achieved by filtering a benzene solution of this compound through400 parts of an adsorbent containing 15% magnesium dioxide and 85%silicon dioxide and washing the adsorbent with a 1:1 mixture of ether inbenzene. On concentration of the eluate and recrystallization of theresidue from benzene and petroleum ether the compound melts at about198203 C. The rotation of a 0.45% chloroform solution d is +11.l.Infrared maxima are observed at 3.40, 3.50, 3.62, 5.88, 6.90, 7.24, 8.51and 9.62 microns.

A solution of 30 parts of 3-dimethylamino-6-oxoconanine in 250 parts ofmethanol is refluxed and stirred with 114 parts of iodomethane for 12hours under nitrogen. The mixture is then concentrated to about 120parts and allowed to cool to room temperature. The crystals arecollected on a filter, washed with methanol and dried to yield thebismethiodide of 3-dimethylarnino- 6-oxoconanine melting above 300 C.

55 parts of the bismethiodide of 3-dimethylamino-6 oxoconanine arestirred and refluxed under nitrogen with a solution of 14 parts ofpotassium metal in 240 parts of tertiary butanol. After 4.5 hours 120parts of solvent are removed by distillation and the residue is dilutedwith 540 parts of dry toluene and the distillation is continued. Thisprocess is repeated twice using two 240 part portions of anhydroustoluene. When a total of 900 parts of solvent has been distilled off themixture is cooled in ice and stirred with ice and water. The organiclayer is separated by decantation and washed with water. The combinedaqueous phases are extracted with ether. The ether extract is Washedwith water and combined With the toluene layer. The organic extracts aredried over anhydrous sodium sulfate and concentrated to dryness undervacuum on the steam bath. On recrystallization from acetonitrile thereis obtained 3,5-cyclo-18-dimethylamino-20-pregnen-6-one melting at about73-75 C., resoldifying and remelting at 84-85" C. An additionalcrystalline modification obtained in elongated prisms melting at about8788 C., can be isolated from methanol.

A mixture of 3 parts of 3,5-cyclo-1S-dimethylarnino- 20-pregnen-6-one in30 parts of benzene and 12 parts of methyl p-toluenesulfonate isrefluxed for 3 days. The solvent is then removed under nitrogen on thesteam bath and ether is added slowly. The resulting precipitate iscollected on a filter and washed with a mixture of ether in benzene anddried. The resulting amorphous product is triturated with boilingbenzene and the mixture is allowed to cool. There is thus obtained3,5-cyclo-18- trimethylammonium-Z0-pregnen-6-one p-toluenesulfonatemelting at about 205210 C.

To a solution of 2.7 parts of 3,5-cyclo-18-trimethylammonium-ZO-pregnen-G-one p-toluenesulfonate in 7.8 parts of anhydrousacetonitrile and 8 parts of benzene are added 1.5 parts of osmiumtetroxide. The mixture is maintained at room temperature for 40 hours,after which it is diluted with 8 parts of acetonitrile and treated withexcess hydrogen sulfide for 35 minutes. The resulting mixture isfiltered and the precipitate is washed with acetonitrile, benzene andethanol. The filtrate is taken to dryness to yield3,5-cyclo-l8-trirnethylammonium-20,21- dihydroxypregnan-6-onep-toluenesulfonate.

To 0.7 part of this quaternary salt is added a solution of 1 part ofpotassium in 20 parts of tertiary butanol. The mixture is stirred withreflux under nitrogen for 2 hours, then diluted with water andconcentrated under nitrogen on the steam bath. The aqueous residue isextracted with ether and the ether extract is washed with 20% aqueoussodium hydroxide, then with cold 3% aqueous hydrochloric acid, sodiumhydroxide, and water and dried. On evaporation of the solvent apartially crystalline, neutral product is obtained which is trituratedwith ether. The 3,5-cyclo-18,20-epoxy-2l-hydroxypregnan-6-one thusobtained has the structural formula.

oH, oH-orno11 on,

Recrystallized from benzene and then from methanol it melts at about185-188 C. Infrared maxima are observed at 2.84, 3.40, 3.46, 5.95, 7.26,7.67, 8.56, 8.83, 9.61, 9.70, and 11.95 microns. The mother liquorcontains 3,5 -cyclo-l 8,2 l-epoxy-20-hydroxypregnan-6-one.

The hydrochloric acid extract, after treatment with excess aqueoussodium hydroxide yields the crude 3,5-cyclo-l8-dimethylamino-20,21-dihydroxypregnan 6 one melting at aboutl-195 C. The infrared spectrum was identical with that of a productobtained directly from the treatment of3,5-cyclo-1S-dimethylamino-ZO-pregnen- 6-one with osmium tetroxide.

Example 2 A solution of 0.241 part of 3,5-cyclo-18,20-epoxy-21-hydroxypregnan-6-one in 1.6 parts of pyridine is stirred with 0.226 partof p-toluenesulfonyl chloride. After 10 hours the mixture is cooled inice and treated With 0.2 part of water for 30 minutes. The solution isthen taken up in ether, washed successively With aqueous sulfuric acid,water, aqueous sodium hydroxide and again with water and dried. Theether is removed under nitrogen on the steam bath and the residue iscrystallized from ether to yield the p-toluenesulfonate of3,5-cyclo-18,20- epoxy-21-hydroxypregnan-6-one melting at about 142- 143C.

Example 3 A solution of 15.5 parts of the p-toluenesulfonate of3,5-cyclo-18,20-epoxy-2l-hydroxypregnan-6-one in 350 parts of a 30%solution of dimethylamine in anhydrous acetonitrile is maintained atroom temperature for a week and then is taken to dryness at roomtemperature under vacuum. The residue is taken up in a mixture of etherand benzene and then separated into neutral and basic fractions byextraction with 0.5 N aqueous hydrochloric acid. The neutral fractioncontains a small amount of unconverted starting material. The acidicextract is rendered alkaline and recrystallized from methanol and thenfrom a mixture of benzene and petroleum ether to yield3,5-cyclo-18,20-epoxy-21-dimethylaminopregnan-6- one which melts atabout 145147 C. Infrared maxima are observed at 3.37, 3.41, 3.47, 3,56,5.94, 6.87, 7.26,

51 7.69, 9.62, 9.75, 9.82, 9.94 and 10.09 microns. compound has thestructural formula Example 4 The Substitution of an equivalent amount ofdiethylamine for the dimethylamine used in the preceding example yields3,5-cyclo-18,20-epoxy-21-diethylaminopregnan-6- one. The ultravioletabsorption spectrum shows a maximum at 208 millimicrons and has amolecular extinction coefiicient of about 5600. Infrared maxima areobserved at 3.37, 3.41, 3.47, 3.56, 5.94, 6.87, 7.26, and 9.75 microns.

Example A solution of 0.16 part of 3,5-cyclo-18,20-epoxy-21-dimethylaminopregnan-6-one in 1 part of benzene is treated with 2.7parts of an 0.16 molar solution of peroxybenzoic acid in benzene. Afterstanding for minutes at 5 C. the solution is diluted with ether andextracted with 2% aqueous sodium hydroxide. This extract is washed withether and then extracted with chloroform. The chloroform extract isconcentrated under vacuum and the resulting gum is crystallized fromacetone. There is thus obtained 3,5-cyclo-18,20-epoxy-21-dimethylaminopregnan-6-one N-oxide in elongated prisms which melt atabout 188-190 C. with decomposition after previous sintering at about185 C. The infrared absorption spectrum shows a broad and strong band at2.8 to 3.3 microns and a strong peak at 5.9 microns; other maxima areseen at 6.85, 7.26, 7.70, 8.83, 9.70, 9.8 0, and 10.83 microns.

Example 6 At 170 C. 0.64 part of3,S-cyclo-18,20-epoxy-21-dimethylaminopregnan-6-one N-oxide are addedrapidly to 21.5 parts of anhydrous tertiary p-butyl toluene. The mixtureis rapidly brought to reflux, stirred and slowly distilled undernitrogen so that after 25 minutes about 9 parts of distillate arecollected. The solution is then quickly cooled to room temperature. Thesolvent is removed under vacuum at a temperature below 70 C. Theresidue, which solidifies completely, is triturated with ether to yield3,5-cyclo-l8,20-epoxy-20-pregnen-6-one melting at about 174-185 C. Verystrong infrared maxima are obtained at 9.71 and 12.78 microns; othermaxima are seen at 3.32, 3.42, 3.50, 5.94, 5.99, (shoulder) 6.37, 7.30,7.60, 7.74, 8.1, 8.62 and 11.43 microns. The compound has the structuralformula sulfonate of 3,5-cyclo-18,20-epoxy-21-hydroxypregnan-6- one in 2parts of toluene is treated with a solution of 0.08 part of potassiummetal in 2 parts of tertiary butanol under nitrogen. mixture is cooled,diluted with ether, washed with water, dried and taken to dryness, toyield a mixture of 3,5 cyclo-18,20-epoxy-l7-pregnen-6-one and3,5-cyclo-18,20- epoxy-20-pregnen-6-one.

Example 7 A solution of 0.2 part of 3,5-cyclo-18,20-epoxy-20-pregnen-6-one in 5 parts of dioxane is treated with 1 part of 0.5 Naqueous hydrochloric acid. The homogeneous solution is permitted tostand at room temperature for minutes and is then diluted with ether andwashed successively with 0.5 N aqueous hydrochloric acid, 5% aqueoussodium hydroxide, and water. After drying over anhydrous sodium sulfate,the solvent is evaporated on a steam bath under nitrogen and the residueis recrystallized from butanone to yield 3,5 -cyclo-18,20-epoxy-20-hydroxypregnan-6-one melting at about 162177 C. Strong infraredmaxirna are observed at 2.90 and 5.98 microns, other maxima at 3.38,3.42, 3.48, 6.87, 7.27, 7.68, 8.88, 9.73 and 11.24 microns. The compoundhas the structural formula 0, CH CH -OH The evidence points to the factthat the product is obtained as a stable hemiketal rather than as the3,5-cyelo- 18-hydroXypregnan-6-one.

Example 8 A solution of 1.44 parts of 3,5-cyclo-18,20-epoxy-21-dimethylaminopregnan-6-one in 10 parts of commercial tetrahydrofuran isadded to a solution of 1.5 parts of lithium aluminum hydride in 25 partsof tetrahydro furan. After refluxing under nitrogen for 30 minutes themixture is stirred for 4 hours at room temperature and then treatedsuccessively with 1.6 parts of water and 6 parts of tetrahydrofusran,1.2 parts of 20% aqueous sodium hydroxide and 5.5 parts of water. TheWhite suspension is diluted with an equal volume of ether, stirred andcooled to room temperature during 15 minutes. It is then filtered andthe inorganic precipitate is washed thoroughly with ether. The combinedfiltrate and the Washings are evaporated to a small volume on the steambath under nitrogen. On cooling a precipitate forms which is stirredwith a large amount of water. Crystals are then collected on a filter,washed with water and dried under vacuum at 60 C. After trituration withother the 3,5-cyclo-18,20-epoxy 21-dimethylaminopregnan-6-ol melts atabout 133-137" C. Infrared maxima are observed at 3.04, 3.38, 3.42,3.50, 3.59, 6.80, 6.85, 9.24, 9.50, 9.72, 9.78, and 11.78 micronsExample 9 A solution of 1.32 parts of the 3,5-cyclo-18,20-epoxy-21-dimethylaminopregnan-6-ol, obtained in the preceding example, in 35.5parts of 98% formic acid is maintained at room temperature for 48 hoursand then concentrated under vacuum at 20 C. The residue is diluted with20 parts of methanol, neutralized with 50% aqueous potassium hydroxideand then treated with 5 parts of 50% aqueous potassium hydroxide. Themixture is heated at 60 C. for 3 hours and then concentrated to a smallvolume under nitrogen on a steam bath. The resulting crystallinesuspensionis extracted with ether and the ex- After refluxing for 1hour, the.

tract is washed with water, dried, and taken to dryness under nitrogen.The crystalline residue is recrystallized from benzene to yield18,20-epoxy-2l-dimethylamino-S- pregnen-3-ol melting at about 160163 C.Infrared maxima are observed at 2.85, 3.40, 3.48, 3.51, 3.68, 6.85,9.20, 9.46, 9.60 and 11.75 microns. The compound has the structuralformula By subjecting to the procedure of the preceding example3,5-cyclo-18,20-epoxy-21-diethylaminopregnan6- one there is obtained the3,5-cyclo-18,20epoxy-21-diethylarninopregnan-6-ol which shows infraredmaxima at 3.00, 3.38, 3.42, 3.50, 3.59, 6.80, and 9.72 microns. Ontreatment with formic acid and then with base as in the foregoingprocedure there is obtained 18,20-epoxy 21-diethylamino-5-pregnen-3-olwhich shows infrared maxima at 2.85, 3.40, 3.48, 3.51, 3.68, 6.85, and9.60 microns.

Example 10 A solution containing 0.73 part of 18,20-cpoxy-21-dimethylarnino-5-pregnen-3-ol in 19 parts of toluene and 7.1 parts ofcyclohexanone is distilled under nitrogen until 4 parts of distillateare collected. The stirred mixture is then treated with 0.8 part ofaluminum isopropoxide and the distillation is continued for 35 minuteswhile 4 additional parts of distillate are collected. The gelatinousmixture is quickly cooled under ice and stirred for 45 minutes with 20parts of 0.5 N aqueous hydrochloric acid and parts of ether. The mixtureis diluted with more ether and extracted with 0.5 N aqueous hydrochloric acid. The extract is washed with ether and the pH is raised to910 by addition of cold aqueous potassium hydroxide. The base is thenquickly extracted with ether. The ether extract is Washed with water,dried and taken to dryness under nitrogen. The residue is then driedunder vacuum to yield 18,20-epoxy-2l-dimethylamino-4pregnen-3-onemelting at about l2l.5l23 C. Infrared maxima are observed at 3.41, 3.50,3.60, 5.95, 6.20, 6.80, 6.91, 7.87, 9.61, 11.5 and 11.80 microns. Thecompound has the structural formula orr mcrn om CH CH Example 11 Asolution of 0.45 part of 18,20-epoxy-21-dimethylamino-4-pregnen-3-one in3 parts of benzene is treated by slow portionwise addition 5.2 parts ofcold 0.23

8 molar peroxybenzoie acid solution in benzene. After 1 minute themixture is diluted with ether and extracted with a solution of 0.2 partof sodium hydroxide in 15 parts of water and then with water. Thecombined aqueous extracts are then extracted with chloroform. Thechloroform solution is concentrated to dryness under vacuum at atemperature of less than 40 C. and the resulting residue isrecrystallized from acetone to yield 18,20-epoxy-2l-dirnethylamino 4pregnen-3-one N-oxide melting at about 185187 C. with decomposition. Anultraviolet absorption maximum at 240.5 millimicrons shows an extinctioncoefficient of 15,300. Infrared maxima are observed at 2.80 to 3.30,3.42, 3.50, 5.95, 6.18, 6.90, 9.67, and 9.77 microns.

Example 12 At a temperature of 150 C., 0.41 part of 18,20-epoxy-21-dimethylamino 4 pregnen-3-one N-oxide are added to 22 parts ofanhydrous tertiarybutylbenzene. The mixture is quickly brought toboiling and slowly distilled under nitrogen until after about 20 minutes10 parts of distillate are collected. The solution is then rapidlycooled in ice and taken to dryness under vacuum at a temperature below60 C. The residual gum shows a strong infrared absorption in the regionof 12.7 microns characteristic of a vinyl ether. Other infrared maximashown by 18,20-epoxy-4,20-pregnadien-3-one are observed at 3.40, 3.49,5.95, 6.18, 9.58, and 11.56 microns. The compound has the structuralformula /0 CH QHNA A solution of 18,20-epoxy-4,20-pregnadien3-0ne, asobtained in the preceding example, in 10 parts of dioxane is treated for1 hour with 5 parts of 0.5 N aqueous hydrochloric acid. The mixture isthen diluted with ether, washed successively with 0.5 N aqueoushydrochloric acid, Water, aqueous sodium hydroxide and again with Waterand dried. The resulting solution is concentrated to dryness undernitrogen to yield 18,20-epoxy-20-hydroxy-4-pregnen-3-one which, ontrituration with ether, followed by recrystallization from butanonegives needles melting at about 173182 C. The ultraviolet absorptionspectrum shows a maximum at 241 millimicrons with a molecular extinctioncoefiicient of about 17,100. Infrared maxima are observed at 2.92, 3.42,3.48, 5.95, 6.18, 8.93, 9.62, 10.71, 11.18 and 11.76 microns. Thecompound has the structural formula 0 on on. o-on The fact that theinfrared spectrum does not show a maximum characteristic for a saturatedcarbonyl group in the region of 5.8 to 5.9 microns indicates that thismaterial exists entirely in the hemi-ketal form rather than as18-hydroxyprogesterone.

9 What is claimed is: 1. A compound of the structural formula wherein Xis a member of the class consisting of 0 OHOH N(1owera1ky1) c'fi-cmliwm), C=CH and C(0H)CH groups 2. 18,20-epoxy-21-di(1oweralkyl)amino-4-pregnen-3- one.

3. 18,20-epoxy-21-dimethylamino-4-pregnen-3-one. 4.18,20-epoXy-21-dimethy1amino-4-pregnen-3-one N- 10 oxide.

5. 18,20-epoxy-4,20-pregnadien-3-one. 6.18,20-epoxy-20-hydroxy-4-pregnen-3-one. 7. 18,20-epoXy-21-di(loweralkyDamino-S-pregnen-3-o1.

15 No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA